White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies / asthma due to the development of an unwanted or excessive type of immune response to substances in our environment and in autoimmune diseases that result from the inappropriate attack of these cells on the body?s own tissues. T cells develop in a gland called the thymus, where they learn to distinguish the natural components of the body from the mutant proteins in tumor cells or those produced by infectious agents. This education process involves allowing cells with useful forms of surface proteins called receptors to mature into functional T cells and eliminating cells with inappropriate receptors before they can become dangerous. This process must work properly to generate the set of T cells needed for effective responses to invading organisms and cancer, without allowing development of those cells harmful to normal body tissues. One goal of our work is to understand how this "education / selection" process occurs and the stages through which the maturing T cells pass. Because T cells see foreign substances (antigens) in the form of peptide-major histocompatibility complex (MHC) molecule complexes on cell surfaces, we also wish to know how such materials interact with the T cell receptor to guide the development of T cells in the thymus and the activities of mature T cells in the body. To accomplish these goals, we examine the cellular, biochemical, and genetic events involved in T-cell development. In the past year, we have documented changes in the function of the T cell receptor during thymocyte maturation that allow T- cells to make a useful functional distinction between foreign substances (antigens) to which immune responses are desirable and self proteins, to which immune responses are undesirable and potentially harmful. We have also expanded our knowledge of the role(s) of MHC molecule interaction with T-cell receptors in guiding the various stages of T-cell development, and of the contribution of various antigen unspecific signaling pathways to this developmental process. Finally, we have begun to establish a large catalog of genes whose express varies significantly among the several well-defined stages of T-cell maturation and are on our way to developing methods for the rapid functional analysis of each of these genes for their role(s) in controlling T-cell differentiation and function.